1-Benzoxepino[4,3-c]pyridines

ABSTRACT

The present invention is concerned with 11-oxo-1-benzoxepino[4,3-c]pyridines of Formula I: ##STR1## wherein R 1  and R 2  may be hydrogen, lower alkyl, cyano, carboxamido, carboxy, ethoxycarbonyl or tetrazolyl and R 3  may be hydrogen, lower alkyl, halogen, hydroxy or lower alkoxy. 
     These compounds are indicated in the management of allergic conditions such as bronchial asthma, hay fever and the like.

The present invention is concerned with11-oxo-1-benzoxepino[4,3-c]pyridines of Formula I: ##STR2## wherein R₁and R₂ may be hydrogen, lower alkyl, cyano, carboxamido, carboxy,ethoxycarbonyl or tetrazolyl and R₃ may be hydrogen, lower alkyl,halogen, hydroxy or lower alkoxy.

In the above definition for R₁, R₂ and R₃, lower alkyl and the loweralkyl portion of lower alkoxy are meant to have 1-6 carbon atoms asexemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl,isobutyl and so on.

Included among the scope of the present invention are pharmaceuticaldosage forms comprising as an active ingredient the above compound.

Also included within the present invention are novel processes for theproduction of Compound I.

The above compounds exhibit the properties of preventing allergicmanifestations, for example, in tests conducted according to theprocedures described by I. Mota, Life Sciences, 7: 465 (1963) and Z.Ovary and O. Bier, Proc. Soc. Exptl. Biol. Med., 81: 584 (1952), thesecompounds exhibit the prevention of allergic manifestations in rats at adose of about 2 mg/kg orally.

The compounds of the present invention are indicated in the managementof allergic manifestations such as bronchial asthma, hay fever and thelike. Generally speaking, the compounds are administered orally at adose of about 2 mg per kg body weight, up to three times daily. Thisdosage regimen may be varied depending upon the age, sex and weight ofthe patient being treated by methods well-known to the healing arts. Aswith any management of allergic conditions, the precise dosage levelmust also be titrated and individualized.

In order to administer these compounds, they are formulated with inertdiluants such as lactose and compounded into dosage forms such astablets, by methods well-known in pharmaceutical technology.

According to the present invention, the above Compound I is obtained bytreating a compound of structural formula II: ##STR3## with3-aminocrotononitrile under reflux conditions in a suitable solvent suchas a lower molecular weight alcohol, typically ethyl alcohol. Thecompound obtained has the following structural formula: ##STR4##Compound III, having the cyano group, can be converted to othercompounds of this invention by methods well-known in the art. Forexample, acid hydrolysis yields those compounds of the invention inwhich R is carboxy or converted to tetrazolyl with sodium azide.

Starting Compound II is prepared in accordance with the procedure setout in U.S. Pat. No. 3,991,082, whereas 3-aminocrotononitrile is a knowncompound available from commercial sources such as Aldrich ChemicalCompany.

In order to illustrate the practice of the present invention, thefollowing examples are included. In the examples, temperatures are indegrees Centigrade.

EXAMPLE 1 ##STR5##5,11-Dihydro-3-methyl-11-oxo-1-benzoxepino[4,3-c]pyridine-4-carbonitrile.

A solution of 8.16 g (0.04 mole) of2,3-dihydro-5-hydroxy-3-oxo-1-benzoxepin-4-carboxaldehyde, 4.92 g (0.06mole) of 3-aminocrotononitrile and 50 ml of absolute ethanol wasmaintained at reflux for 10 min. and cooled. The separated crystals werefiltered, washed with 10 ml ethanol and dried, wt. 5.2 g (52%); mp124°-126°. Recrystallization was effected by dissolution in 75 ml of 50%dichloromethane-ethanol and removal, by distillation, of most of thedichloromethane. The pure product separated as tan crystals; wt. 2.9 g(29%), mp 126°-128°.

Anal. Calcd. for C₁₅ H₁₀ N₂ O₂ : C, 71.99; H, 4.03; N, 11.20. Found: C,71.85; H, 4.10; N, 11.22.

EXAMPLE 2 ##STR6##5,11-Dihydro-3-methyl-11-oxo-1-benzoxepino[4,3-c]pyridine-4-carboxylicacid.

A quantity of 7.5 g (0.03 mole) of5,11dihydro-3-methyl-11-oxo-1-benzoxepino[4,3-c]pyridine-4-carbonitrilewas dissolved in 100 ml of 50% sulfuric acid. The solution was heated at140°-145° for one-half hour and diluted with 400 ml of ice water. Theseparated crystals were filtered, washed well with water and dried; wt.6.2 g. Addition of 40% potassium hydroxide to pH ca. 3 precipitated asecond crop of the same material (via tlc); wt. 1.1 g. The combinedcrude products were dissolved in 200 ml of 40% sodium bicarbonate. Thesolution was charcoaled, filtered and acidified with conc. hydrochloricto pH 4 to precipitate product; wt. 5.0 g (62%); mp 216°-218°.Recrystallization from methanol gave pure product with the same meltingpoint.

Anal. Calcd. for C₁₅ H₁₁ NO₄ : C, 66.91; H, 4.12; N, 5.20. Found: C,66.88; H, 4.25; N, 5.13.

EXAMPLE 3 ##STR7##3-Methyl-4-(1H-tetrazol-5-yl)-1-benzoxepino[4,3-c]pyridin-11(5H)-one.

To a stirred mixture of 2.5 g (0.01 mole) of5,11-dihydro-3-methyl-11-oxo-1-benzoxepino[4,3-c]pyridine-4-carbonitrile,1.95 g (0.03 mole) of sodium azide and 50 ml of tetrahydrofuran, added,under nitrogen and slowly, 1.5 g of aluminum chloride. The mixture wasstirred for 1 hour at reflux, cooled and treated with another 1.5 g ofaluminum chloride. The mixture was maintained at reflux for 48 hours andcautiously added to 150 ml of ice water. Conc. hydrochloric acid (5 ml)was added and the crude solid was filtered. This was stirred with 200 mlof 3% sodium bicarbonate and the insolubles were filtered. The filtratewas acidified with conc. hydrochloric acid to pH 3. The separated whitesolid was filtered, washed with water and dried, wt. 0.15 grams (5%); mp180°-182°. Recrystallization from methanol gave pure product; mp183°-185°.

Anal. Calcd. for C₁₅ H₁₁ N₅ O₂ : C, 61.43; H, 3.78; N, 23.88. Found: C,61.26; H, 3.94; N, 23.79.

We claim:
 1. A compound of the formula: ##STR8## wherein R₁ may behydrogen or lower alkyl, R₂ may be cyano, carboxamido, carboxy orethoxycarbonyl, and R₃ may be hydrogen, lower alkyl, halogen, hydroxy orlower alkoxy.
 2. A compound according to claim 1 which is5,11-dihydro-3-methyl-11-oxo-1-benzoxepino[4,3-c]pyridine-4carbonitrile.3. A compound according to claim 1 which is5,11-dihydro-3-methyl-11-oxo-1-benzoxepino[4,3-c]pyridine-4-carboxylicacid.